CN109512820A - Application of the iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus - Google Patents
Application of the iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus Download PDFInfo
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- CN109512820A CN109512820A CN201811487353.3A CN201811487353A CN109512820A CN 109512820 A CN109512820 A CN 109512820A CN 201811487353 A CN201811487353 A CN 201811487353A CN 109512820 A CN109512820 A CN 109512820A
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The present invention relates to application of the iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus, belong to pharmaceutical technology field.The present invention provides application of the iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus.ICRT14 compound of the invention can reduce random blood glucose level and fasting blood glucose level, reduce glycated hemoglobin levels, reduce lactate dehydrogenase levels, can be used to prepare the drug for the treatment of type-1 diabetes mellitus, provide new medicament selection for the treatment of type-1 diabetes mellitus.
Description
Technical field
The present invention relates to application of the iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus, belong to medical science
Field.
Background technique
Diabetes (Diabetes mellitus, DM) are one group as caused by insulin secretion and (or) effect defect, with
Chronic blood glucose level increases the metabolic disease being characterized.It can be divided into two types: I type or insulin-dependent diabetes mellitus
With II type or non-insulin-dependent diabetes mellitus.Type-1 diabetes mellitus is to be destroyed to cause by pancreas islet B cell, and type-2 diabetes mellitus is
It is caused since insulin function is impaired.Type-1 diabetes mellitus is the autoimmune disease for the islet p-cell destruction that T cell mediates, more
It is sent out in child or adolescent's phase, while also showing type-1 diabetes mellitus all age group especially climacteric.Type-1 diabetes mellitus need to answer
Blood glucose is controlled with exogenous insulin, currently without radical cure method.Therefore, it establishes in addition to insulin injection, other are effective
Treatment method and means extend patient's service life, have a very important significance for improving quality of life in patients with diabetes.
ICRT14 is a kind of novel β-catenin pathway inhibitor, has molecule small, fat-soluble high, easy by thin
The features such as after birth, by inhibiting β-catenin to play a role in conjunction with nuclear factor TCF/LEF family downstream.At present
In vivo and in vitro discovery, iCRT14 plays antitumor, antiviral life by inhibition tumor cell proliferation, suppressing virus replication
Object effect.The structural formula of iCRT14 is as follows:
But currently, iCRT14 it is not immediately clear using the rear influence to diabetic sugar disorders of lipid metabolism.Therefore, this project
Type-1 diabetes mellitus mouse model is established using streptozotocin (Streptozocin, STZ), it is intended to study iCRT14 to diabetic sugar
The influence of disorders of lipid metabolism.
Summary of the invention
ICRT14 compound is provided and is controlled in preparation it is an object of the invention to overcome above-mentioned the deficiencies in the prior art place
The application in the drug of type-1 diabetes mellitus is treated, iCRT14 compound of the invention can reduce random blood glucose level and fasting blood syrup
It is flat, glycated hemoglobin levels are reduced, lactate dehydrogenase levels are reduced.
To achieve the above object, the technical scheme adopted by the invention is as follows: the present invention provides iCRT14 compounds to prepare
Treat the application in the drug of type-1 diabetes mellitus.
As the preferred embodiment of application of the present invention, the drug of the treatment type-1 diabetes mellitus is to reduce random blood
The drug of sugar level and fasting blood glucose level.
As the preferred embodiment of application of the present invention, the drug of the treatment type-1 diabetes mellitus is to reduce saccharification blood
The drug of red eggs white level.
As the preferred embodiment of application of the present invention, the drug of the treatment type-1 diabetes mellitus is to reduce lactic acid to take off
The drug of hydrogen enzyme level.
The present invention also provides a kind of drug for treating type-1 diabetes mellitus, the drug contains iCRT14 compound.
The preferred embodiment of drug as treatment type-1 diabetes mellitus of the present invention, the drug also contain medicinal load
Body.
The preferred embodiment of drug as treatment type-1 diabetes mellitus of the present invention, the dosage form of the drug are capsule
Agent, tablet, pill, granule, oral liquid or injection.
Compared with prior art, the invention has the benefit that iCRT14 compound of the invention can reduce random blood sugar
Horizontal and fasting blood glucose level reduces glycated hemoglobin levels, reduces lactate dehydrogenase levels, can be used to prepare treatment I type
The drug of diabetes.
Detailed description of the invention
Fig. 1 is the statistical analysis figure of each group mouse weight variation in embodiment 1.
Fig. 2 is the statistical analysis figure of each group mouse random blood sugar variation in embodiment 1.
Fig. 3 is the statistical analysis figure of each group mouse weight variation in embodiment 2.
Fig. 4 is the statistical analysis figure of each group mouse random blood sugar variation in embodiment 2.
Fig. 5 is the statistical analysis figure of each group mouse fasting blood-glucose variation in embodiment 2.
Fig. 6 is that 8 weeks each group glucose tolerance in mice variation diagrams are administered in embodiment 2.
Fig. 7 is that 20 weeks each group glucose tolerance in mice variation diagrams are administered in embodiment 2.
Fig. 8 is the statistical analysis figure of each group glucose tolerance in mice variation in embodiment 2.
Fig. 9 is the statistical analysis figure of each group mouse glycated hemoglobin levels variation in embodiment 2.
Figure 10 is the statistical analysis figure of each group mouse triglyceride levels variation in embodiment 2.
Figure 11 is the statistical analysis figure of each group mouse total cholesterol level variation in embodiment 2.
Figure 12 is the statistical analysis figure of each group Mouse Lactate Dehydrogenase level variation in embodiment 2.
Specific embodiment
Purposes, technical schemes and advantages in order to better illustrate the present invention, below in conjunction with the drawings and specific embodiments pair
The present invention is described further.
In following embodiments, unless otherwise specified, the routine that technological means used is well known to those skilled in the art
Means, reagent and material in the application can from the market or other public channels obtain.In the present invention, statistical analysis is more
Comparison among groups one-way analysis of variance, multiple samples compare selection Tukey two-by-two and examine, and P < 0.05 thinks that difference has statistics
Meaning is analyzed.
The influence for the type-1 diabetes mellitus mouse blood sugar that 1 short-term administration iCRT14 of embodiment induces streptozotocin
1. medicine ordinance: 2mL PEG400 (polyethylene glycol 400) is added in 100mg iCRT14, and ultrasound is mixed to milk yellow oil
Shape liquid adds 8mL PBS (phosphate buffered saline solution), and continuing ultrasound is uniform light yellow liquid, configures 10mg/mL's
Mother liquid medicine is then diluted to working solution using the mixed liquor of 80%PBS and 20%PEG400 and is injected.
2. animal model: 0.2% streptozotocin is injected intraperitoneally in 7~8 week old C57BL/6 male mices
(Streptozocin, STZ) 45mg/kg/day, continuous injection 5 days.Normal group gives the citrate buffer solution of equivalent.Injection knot
Beam surveys mouse blood sugar after 72 hours, mouse of the blood sugar concentration higher than 16.7mmol/L is considered as modeling success.
3. test is grouped: 4th week after diabetic mouse model modeling success, detection mouse blood sugar continue, stablize raising,
Test grouping is carried out, is grouped as follows:
(1) CON: isometric solvent is injected intraperitoneally in Normal group, normal mouse；
(2) CON+iCRT40: iCRT14 40mg/kg is injected intraperitoneally in normal administration group, normal mouse；
(3) T1DM (Type 1diabetes mellitus): type-1 diabetes mellitus group, diabetic mice intraperitoneal injection are isometric
Solvent；
(4) iCRT14 5mg/kg group is administered in T1DM+iCRT5:I patients with type Ⅰ DM, and 5mg/kg is injected intraperitoneally in diabetic mice
iCRT14；
(5) iCRT14 10mg/kg group is administered in T1DM+iCRT10:I patients with type Ⅰ DM, and 10mg/ is injected intraperitoneally in diabetic mice
kg iCRT14；
(6) iCRT14 20mg/kg group is administered in T1DM+iCRT20:I patients with type Ⅰ DM, and 20mg/ is injected intraperitoneally in diabetic mice
kg iCRT14；
(7) iCRT14 40mg/kg group is administered in T1DM+iCRT40:I patients with type Ⅰ DM, and 40mg/ is injected intraperitoneally in diabetic mice
kg iCRT14。
Every group of 20 mouse, injection drug 1 time daily, successive administration 14 days, during administration, normal diet, free water.
4. Testing index
After administration 7 days, after 14 days, each group mouse weight is weighed；Mouse random blood sugar is detected using blood glucose meter simultaneously.
Caudal vein surveys blood glucose method: after Animal Anesthesia, mouse tail venous blood collection is pierced through, when drop of blood goes out more than 1 μ L
It drips on Yu Wenhao type blood glucose meter special test paper, measures blood glucose value, take cotton balls hemostasis by compression after blood.
5. test result
Investigate the shadow of the type-1 diabetes mellitus mouse weight, random blood sugar giving the iCRT14 of various dose in short term and induce STZ
It rings.
(1) death rate
2 weeks record mouse death rates of successive administration, as the result is shown except intraperitoneal injection 20mg/kg iCRT14 (T1DM+
ICRT20 group), outside the diabetic mice of 40mg/kg iCRT14 (T1DM+iCRT40 group), each group mouse state is normal, has no dead
It dies.T1DM+iCRT20 group dead 2 altogether, the death rate 10%；T1DM+iCRT40 group dead 6 altogether, the death rate 30%.
(2) weight
The statistical analysis figure of each group mouse weight variation is as shown in Figure 1, wherein * * indicates P < 0.01, ## compared with CON group
Indicate P < 0.05 compared with T1DM group.As shown in Figure 1, after successive administration 14 days, compared with CON group, CON+iCRT40 group weight
Have no significant change, T1DM group weight significantly reduces 22.9% (P < 0.01)；With the increase of dosage, T1DM+iCRT20
Group weight weight loss 8.1% compared with T1DM group, T1DM+iCRT40 group compared with T1DM group weight loss 15.51% (P <
0.05)。
(3) random blood sugar
Each group mouse random blood sugar variation statistical analysis figure it is as shown in Figure 2, wherein * * indicate compared with CON group P <
0.01, # indicates P < 0.01 compared with T1DM group.As shown in Figure 2, after successive administration 14 days, compared with CON group, CON+iCRT40
Group blood glucose does not have significant change, and T1DM group blood glucose is significantly raised (P < 0.01)；Diabetes give each group mouse of iCRT14 with
T1DM group is on a declining curve compared to random blood sugar, and wherein T1DM+iCRT40 group reduces statistically significant (P < 0.01).
According to short-term administration as a result, selection 2.5,5, the iCRT40 of 10mg/kg carries out long term administration and observes the compound
Blood sugar reducing function and adverse reaction.
The influence for the type-1 diabetes mellitus mouse blood sugar that 2 long term administration iCRT14 of embodiment induces streptozotocin
1. test grouping
4th week after diabetic mouse model modeling success, detection mouse blood sugar continue, stablize raising, carry out test point
Group is grouped as follows:
(1) CON: isometric solvent is injected intraperitoneally in normal solvent group, normal mouse；
(2) CON+iCRT10: 10mg/kg iCRT14 is injected intraperitoneally in normal administration group, normal mouse；
(3) T1DM (Type 1diabetes mellitus): diabetes solvent group, the bodies such as diabetic mice intraperitoneal injection
Product solvent；
(4) 2.5mg/kg iCRT14 is injected intraperitoneally in T1DM+iCRT2.5:iCRT14 low dose group, diabetic mice；
(5) 5mg/kg iCRT14 is injected intraperitoneally in T1DM+iCRT5:iCRT14 middle dose group, diabetic mice；
(6) 10mg/kg iCRT14 is injected intraperitoneally in T1DM+iCRT10:iCRT14 high dose group, diabetic mice.
12 mouse of every group of mouse, daily intraperitoneal injection of drugs 1 time, successive administration 20 weeks.During administration, normal diet,
Free water.
2. Testing index
(1) mouse weight is weighed when being administered 8,20 weeks respectively, while detecting mouse random blood sugar, empty stomach using blood glucose meter
Blood glucose；
(2) respectively when being administered 8,20 weeks, intraperitoneal injection glucose carries out sugar tolerance (IPGTT) detection.1 × PBS preparation
10% glucose and sterilization.16 hours rear molding venous blood samplings of mouse fasting measure fasting blood-glucose, subsequent every mouse with
Glucose is injected intraperitoneally in the dosage of 2mg/g, and 0.5 after injectable dextrose monohydrate, 1,1.5,2h measurement blood glucose level；
(3) it respectively after administration 8 weeks, 20 weeks, puts to death mouse, collect blood preparation, detected using automatic biochemistry analyzer
The content of glycosylated hemoglobin, triglycerides, total cholesterol, glutamic-pyruvic transaminase, glutamic-oxalacetic transaminease, lactic dehydrogenase.
3. test result
(1) death rate
20 weeks records of successive administration observe each group mouse death rate, are showing each group mouse state just in Germicidal efficacy terminal
Often, it is showed no death.
(2) weight
Each group mouse weight variation statistical analysis figure it is as shown in Figure 3, wherein * *, * indicate compared with CON group P <
0.01, # indicates P < 0.05 compared with T1DM group.From the figure 3, it may be seen that during long term administration, normal mouse weight with week old gradually
Increase.Compared with CON group, CON+iCRT10 group mouse weight without significant change, T1DM group mouse weight gradually decrease (P <
0.01).Successive administration 8 weeks, the diabetic mice of 2.5~10mg/kg iCRT14 is given compared with T1DM group, weight there are no
The variation of statistical significance；Successive administration 20 weeks, the diabetic mice of 2.5~10mg/kg iCRT14 was given compared with T1DM group
Weight gradually increases, and wherein the weight gain of T1DM+iCRT10 group is statistically significant (P < 0.05).
(3) random blood sugar
Each group mouse random blood sugar variation statistical analysis figure it is as shown in Figure 4, wherein # indicate compared with T1DM group P <
0.05, ## indicates P < 0.01 compared with T1DM group.As shown in Figure 4, during successive administration, CON group mouse increases random with week old
Glucostasis；CON+iCRT10 group mouse, random blood sugar have no significant change；T1DM group mouse random blood sugar is held with week old increase
Height of continuing rising.Successive administration 8 weeks, the diabetic mice of 2.5~10mg/kg iCRT14 is given compared with T1DM group, blood glucose gradually drops
Low, wherein T1DM+iCRT10 group declines 20% (P < 0.05).Successive administration 20 weeks, compared with T1DM group, give 2.5~10mg/
The diabetic mice random blood sugar of kg iCRT14 is reduced in dose dependent, wherein T1DM+iCRT5 group blood glucose decline 21.7%
(P < 0.05), T1DM+iCRT10 group decline 32.8% (P < 0.01).Illustrate under this model, iCRT14 is to type-1 diabetes mellitus mouse
Random blood sugar has obvious inhibiting effect.
(4) fasting blood-glucose
Each group mouse fasting blood-glucose variation statistical analysis figure it is as shown in Figure 5, wherein # indicate compared with T1DM group P <
0.05, ## indicates P < 0.01 compared with T1DM group.As shown in Figure 5, during successive administration, CON group mouse increases on an empty stomach with week old
Glucostasis；CON+iCRT10 group mouse, fasting blood-glucose have no significant change；T1DM group fasting blood-glucose gradually rises with week old increase
It is high.Successive administration 8 weeks, compared with T1DM group fasting blood-glucose, after giving 2.5~10mg/kg iCRT14, diabetic mice was on an empty stomach
Blood glucose gradually decreases, and wherein T1DM+iCRT10 group declines 35.2% (P < 0.05).Successive administration 20 weeks, give 2.5~10mg/
The diabetic mice of kg iCRT14 fasting blood-glucose compared with T1DM group is reduced in dose dependent, wherein T1DM+iCRT5 group blood
34.0% (P < 0.05) of sugar decline, T1DM+iCRT10 group decline 41.2% (P < 0.01).The results show that iCRT14 is to I type glycosuria
Sick mouse fasting blood-glucose has obvious inhibiting effect；Compared with the influence to random blood sugar, iCRT14 inhibits the effect of fasting blood-glucose
It is more significant.
(5) sugar tolerance
It measures glucose tolerance (Intraperitoneal glucose tolerance test, IPGTT) and carries out curve
Lower area (Area of under curve, AUC) statistics.Administration each group glucose tolerance in mice variation in 8 weeks is as shown in fig. 6, administration 20
All each group glucose tolerance in mice variations are as shown in fig. 7, the statistical analysis figure of each group glucose tolerance in mice variation is as shown in Figure 8, wherein * *
Indicate that P < 0.01 compared with CON group, # indicate that P < 0.05 compared with T1DM group, ## indicate P < 0.01 compared with T1DM group.
By Fig. 6~8 it is found that compared with CON group, CON+iCRT10 group AUC has no significant change；T1DM group AUC obviously rises
High (P < 0.01).Successive administration 8 weeks, compared with T1DM group, T1DM+iCRT10 group mouse AUC declined 23.1% (P < 0.05).Even
Continuous administration 20 weeks, compared with T1DM group, T1DM+iCRT5 group mouse AUC declines 20.1% (P < 0.05), T1DM+iCRT10 group
AUC declines 33.1% (P < 0.01).
(6) glycosylated hemoglobin (HbAc)
Glycosylated hemoglobin is product of the endoerythrocytic hemoglobin in conjunction with blood glucose in blood of human body, HbAle egg
White test usually can reflect nearly 8~12 weeks glycemic control situations.The statistics of each group mouse glycated hemoglobin levels variation
Analysis chart is as shown in Figure 9, wherein * * indicate with CON group compared with P < 0.01, # indicate compared with T1DM group P < 0.05, ## expression and
T1DM group compares P < 0.01.As shown in Figure 9, successive administration 8 weeks, T1DM group HbAc significantly increase (P < 0.01) compared with CON group；
After giving 2.5~10mg/kg iCRT14, diabetic mice HbAc is gradually decreased, but has no statistically significant.Successive administration
20 weeks, compared with T1DM group, 2.5~10mg/kg iCRT14 can dose-dependently reduce diabetic mice HbAc concentration,
15.22% (P < 0.05) of middle T1DM+iCRT5 group mouse HbAc decline, T1DM+iCRT10 group HbAc decline 29.6% (P <
0.01)。
(7) triglycerides (Triglyceride, TG)
The statistical analysis figure of each group mouse triglyceride levels variation is as shown in Figure 10.As shown in Figure 10, with CON group phase
Than triglyceride levels slightly reduce in T1DM group mice serum, but difference does not have statistical significance.Successive administration 8 weeks, 20
In week, compared with T1DM group, 2.5~10mg/kg iCRT14 can raise triglyceride levels, but no significant difference.
(8) total cholesterol (Total cholesterol, CHOL)
The statistical analysis figure of each group mouse total cholesterol level variation is as shown in figure 11.As shown in Figure 11, with CON group phase
Than T1DM group mouse total cholesterol level is increased, but no significant difference.Successive administration 8 weeks, 20 weeks, with T1DM
Group is compared, and 2.5~10mg/kg iCRT14 has no significant effect diabetic mice total cholesterol.
(9) lactic dehydrogenase (LDH)
Lactic dehydrogenase is that one kind is present in cytoplasm, participates in the catalyzing enzyme of glycolysis final step, normally seldom deposits
The cell being damaged when being in blood plasma, but suffering from diabetes can discharge LDH and enter blood, and LDH content in blood plasma is caused to increase.Therefore it is clinical
It is upper to commonly use Serum LDH activity to judge disease and evaluation drug therapy effect.The system of each group Mouse Lactate Dehydrogenase level variation
It is as shown in figure 12 to count analysis chart, wherein * * indicates that P < 0.01 compared with CON group, ## indicate P < 0.01 compared with T1DM group.By scheming
12 it is found that compared with CON group, CON+iCRT10 group Mouse Lactate Dehydrogenase has no significant change, and T1DM group is small after successive administration
Mouse lactic dehydrogenase significantly increases (P < 0.01).Successive administration 8 weeks, 2.5~10mg/kg iCRT14 was to diabetic mice serum
Dehydrogenase Content, which has no, to be significantly affected.Successive administration 20 weeks, compared with T1DM group, 2.5~10mg/kg iCRT14 can agent
Measuring dependence reduces diabetic mice lactic dehydrogenase enzyme concentration, and wherein T1DM+iCRT10 group declines 38.2% (P < 0.01).
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (8)
- Application of the 1.iCRT14 compound in the drug of preparation treatment type-1 diabetes mellitus.
- 2. application as described in claim 1, which is characterized in that the drug of the treatment type-1 diabetes mellitus is to reduce random blood sugar Horizontal and fasting blood glucose level drug.
- 3. application as described in claim 1, which is characterized in that the drug of the treatment type-1 diabetes mellitus is to reduce HbAle The drug of protein level.
- 4. application as described in claim 1, which is characterized in that the drug of the treatment type-1 diabetes mellitus is to reduce lactic dehydrogenase The drug of enzyme level.
- 5. such as the described in any item applications of Claims 1 to 4, which is characterized in that the dosage form of the drug be capsule, tablet, Pill, granule, oral liquid or injection.
- 6. a kind of drug for treating type-1 diabetes mellitus, which is characterized in that the drug contains iCRT14 compound.
- 7. the drug for the treatment of type-1 diabetes mellitus as claimed in claim 6, which is characterized in that the drug also contains pharmaceutical carrier.
- 8. the drug for the treatment of type-1 diabetes mellitus as claimed in claims 6 or 7, which is characterized in that the dosage form of the drug is capsule Agent, tablet, pill, granule, oral liquid or injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113304149A (en) * | 2021-06-23 | 2021-08-27 | 广州医科大学 | Application of compound in preparation of medicine for treating type 2 diabetic cardiomyopathy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009097113A2 (en) * | 2008-01-28 | 2009-08-06 | New York University | Oxazole and thiazole compounds as b-catenin modulators and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009097113A2 (en) * | 2008-01-28 | 2009-08-06 | New York University | Oxazole and thiazole compounds as b-catenin modulators and uses thereof |
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| FLORENCE FIGEAC等: "Neonatal growth and regeneration of β-cells are regulated by the Wnt/β-catenin signaling in normal and diabetic rats", 《AM J PHYSIOL ENDOCRINOL METAB》 * |
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| CN113304149A (en) * | 2021-06-23 | 2021-08-27 | 广州医科大学 | Application of compound in preparation of medicine for treating type 2 diabetic cardiomyopathy |
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